In the following discussion, a number of citations from professional journals are included for the convenience of the reader. While these citations more fully describe the state of the art to which the present invention pertains, the inclusion of these citations is not intended to be an admission that any of the cited publications represent prior art with respect to the present invention.
The ingestion of toxic metals is an extremely serious health problem in the United States, as well as in many other industrialized nations of the world. Poisoning with cadmium, lead and/or mercury, for example, is surprisingly common, affecting about 1 in every 200 persons in this country. This level of public poisoning is unusually high, given society's awareness of the toxicity of these metals.
In general, the metals considered to be toxic to host organisms are the nutritionally-nonessential heavy metals such as cadmium, lead, cesium, arsenic and mercury. These metal elements are toxic when ingested in any amount, and regardless of the route of entry. Their toxicity derives from their capacity to successfully compete with nutritionally-essential metal elements in metabolic pathways, and to form stable coordination complexes with a variety of binding agents (or "ligands") in these pathways. Because there are no known metabolic requirements for these heavy metal elements in animal nutrition, their ingestion is usually associated with undesirable (sometimes severe) side effects. However, as discussed more fully hereinafter, certain other metals which are relatively nontoxic and are, in fact, essential trace mineral elements needed in nutrition, such as, for example, calcium, magnesium, iron, zinc, and copper can, under certain conditions, also be deleterious to the host and the resulting toxicity can be treated using the methods and compounds of this invention.
The serious problem of metal poisoning occurs most frequently in 1) children (commonly from economically deprived families) who are exposed to these toxic metals in contaminated soil, air and dust of the home environment; and in 2) workers in industry who are contaminated by the heavy metals used as reagents in their workplace. Unfortunately, almost all of the toxic heavy metal atoms ingested or adsorbed remain bound in the tissues of these individuals, where they continue to do damage by competing with essential metal elements in metabolic pathways, interfering (often significantly) with the normal development and functioning of the contaminated individual.
The standard therapeutic procedures used today for treating heavy metal poisoning in individuals are slow, often painful, and use chemical reagents which are themselves sometimes very toxic, damaging the kidneys in the process of capturing the heavy metal atoms and transporting them to the bladder for excretion. Examples of such heavy metal binding agents being used in therapy are diethyldithiocarbamate (Berry et al., J. Clin. Oncol. 8: 1585, 1990; also, see review by G. Renoux, J. Pharmacol. 13 (suppl. 1): 95, 1982); 2,3-dimercapto-1-propanol ("Dimercaprol") (U.S. Pat. No. 2,402,665); and N-acetylcysteine (Hjortso et al., Eur. J. Clin. Pharmacol. 39: 29, 1990). This lack of effective, convenient and nontoxic therapeutic agents for treating metal poisoning is a major problem in society. It is one object of this invention to provide a new class of binding agents which are safe and effective and overcome these general problems of the prior art compounds.
However, for a therapeutic agent to be truly effective in treating metal poisoning, it should not only have the capacity to bind metal atoms, but also to inhibit the synthesis of metallothioneins ("MTs"). Toxic metal atoms remain in tissues because the body traps the toxic metals in the tissues with metallothioneins. These are low molecular weight, cysteine-rich proteins with a high affinity for metal atoms (e.g., see the review by D. H. Hamer, Annu. Rev. Biochem. 55: 913, 1986; GK Andrews, Prog. Food Nutr. Sci. 14: 193, 1990). With a half-life of just a few days, the metallothioneins effectively bind metal atoms, sequestering them in the tissues of the body, then passing the metal atoms on to newly synthesized metallothioneins as they themselves begin to degrade. The problem with this physiologic response is that the metallothioneins are only effective at defensively sequestering the metal atoms; they are completely ineffective at removing them from the body of the host. Thus, this metallothionein response by the body does not abrogate the toxic metal problem. For example, the half-life for cadmium in the human body is estimated to be about 30 years (Jones & Cherian, Toxicology 62: 1, 1990); that for lead is considered to be even longer.
Thus, another object of this invention is to provide a class of binding agents which have the capacity not only to bind metal atoms, but also to inhibit the synthesis of new metallothioneins, so that the metal atoms released by the breakdown of old metallothioneins will be captured by the therapeutic agent and removed from the body. To date no effective therapeutic agents are believed to exist which can be used for these dual purposes.
Accordingly, it is a principal object of the present invention to provide a safe and effective method for binding and removing metals from host organisms.
It is another object of the present invention to provide compounds which are effective metal-binding agents which can be employed therapeutically to bind and remove even toxic heavy metals by excretion from a host organism.
It is yet another object of the present invention to use antisense PS-ODNs as sequence-specific inhibitors of metallothionein protein synthesis while they simultaneously bind available metal ions in the tissues being treated.
It is still another object of the present invention to provide pharmaceutical compositions comprising therapeutically effective amounts of a metal binding agent, together with pharmaceutically-acceptable excipients and carriers, in forms capable of chelating metal atoms and being excreted from the body.